Basically substituted 10,5-(epoxymethano) - 10,11 - dihydro - 5h - dibenzo(a,d)cyclohepten-13-ones



United States Patent M US. Cl. 260247.2 6 Claims ABSTRACT OF THE DISCLOSURE The title compounds are prepared by reacting the corresponding ll-bromo compounds with a secondary amine. Geometrical isomers are obtained by reacting 10,11 epoxy 10,11 dihydro H dibenzo[a,d]cycloheptene-S-carboxylic acid with a secondary amine. The compounds are antibacterials and trichomonicidal agents.

This invention relates to novel chemical compounds which have useful biological properties. In particular this invention relates to derivatives of 10,5-epoxymethano)-10,11-dihydro 5H dibenzo[a,d]cyc.lohepten- 13-one of the following generic Formula I:

wherein R and R are the same or different and represent a lower alkyl group containing from 1-6 carbon atoms, or an aralkyl group containing from 7-10 carbon atoms such as, for example, the benzyl, phenethyl, or trimethoxybenzyl groups. In addition the grouping NR R may itself form part of a heterocycle containing from 1-2 hetero atoms, such as, for example, the pyrrolidino, piperidino, 4-(lower alkyl) or 4-phenyl-substituted piperazino, and morpholino rings. This invention also relates to the salts of the compounds of Formula I with pharmaceutically acceptable acids such as, for example, hydrochloric, sulphuric, oxalic, maleic, or tartaric acid. The compounds of Formula I are readily obtained from the reaction of 11-bromo-10,5-(epoxymethano)-10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-13-one of Formula II with secondary amines of formula HNR R wherein R and R are as defined above or the grouping NR, R is as defined above.

More specifically, a mixture of 11-bromo-10,5-(epoxymethano)-10,11-dihydro 5H dibenzo[a,d]cyclohepten- 13-one and a molar excess of a secondary amine of formula HNR R wherein R} and R or the grouping NRR is as defined above and, optionally, an inert solvent such as, for example, benzene, is stirred at a temperature within the range of from 0-50 C. for a period of time of up to one day. The mixture is concentrated to dryness and the residue is extracted with hot water; the water-insoluble residue is purified in a conventional manner such as, for example, by chromatography or crystal- 3,518,263 Patented June 30, 1970 lization, to give the compound of Formula I wherein either R and R or the grouping NR R are as defined above.

Geometrical isomers of the compounds of Formula I are readily prepared by the interaction of 10,11-epoxy- 10,11 dihydro 5H dibenzo[a,d]cycloheptene 5- carboxylic acid of Formula III with a secondary amine of Formula HNR R wherein either R and R or the grouping NR R are as defined above.

More specifically, a mixture of 10,11-epoxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene 5 carboxylic acid, and a molar excess of a secondary amine of formula HNR R wherein either R and R or the grouping NR R are as defined above, and an inert solvent such as, for example, toluene or xylene, is heated at a temperature within the range of from 100-150 C. for a period of time of up to one day, either at atmospheric pressure or in a sealed vessel, to yield, after removal of the solvent and purification of the residue in a conventional manner such as, for example, by chromatography or crystallization, the compounds of Formula I wherein either R and R or the grouping NR R is as defined above.

One of the starting materials for the compounds of this invention, that is 1l-bromo-10,5-(epoxymethano)- 1 0,1 l-dihydro-SH-dibenzo [a,d] cyclohepten-13-one is prepared as decribed in our co-pending U.S. patent application S.N. 539,640 filed Apr. 4, 1966, now Pat. No. 3,361,767. In brief, one molar proportion of bromine is added to SH-dibenzo[a,d]cycloheptene-S-carboxamide, prepared as described by M. A. Davis et al. in J. Med. Chem. 7, 88 (1964), and the resulting dibromo-compound is treated with boiling water to give 1l-bromo- 10,5 (epoxymethano) 10,11 dihydro 5H dibenzo- [a,d]cyclohepten-13-one.

The other starting material for the compounds of this invention, that is 10,11-epoxy-10,1l-dihydro-5Hdibenzo- [a,d] cycloheptene-S-carboxylic acid of Formula III is prepared by the interaction of 11-bromo-10,5-(epoxymethano)-10,l1-dihydro 5H dibenzo[a,d]cyclohepten- 13-0ne with an aqueous solution of an alkali metal hydroxide.

More specifically, ll-bromo 10,5 (epoxymethano)- 10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-13-one is rapidly added to a vigorously stirred molar excess of an alkali metal hydroxide, optionally sodium hydroxide, dissolved in 5-10 times its weight of water, at a temperature within the range of -100 C. The mixture is stirred for a period of up to two hours and then acidified.

The precipitate is collected and purified by crystallization to give the required l0,11-epoxy-l0,1l-dihydro-SH- dibenzo[a,d]cycloheptene-S-carboxylic acid.

The compounds of this invention have valuable biological properties. They are active against a number of gram-positive and gramnegative microorganisms and are antibacterial agents. For such use they are formulated in the form of creams, lotions, or ointments containing from 0.1-1.0 of the active ingredient. Such lotions, creams and ointments are applied topically to the skin from twice to four times daily, over a period of from 5-15 days. Additionally the compounds of Formula I also possess activity against Trichomonas vaginalis and are trichomonicidal agents. For such use they may be formulated in the form of suppositories or vaginal inserts containing from 40-200 mg. of the active ingredient. Such suppositories or vaginal inserts are to be administered twice to four times daily, over a period of from 5 to 15 days.

The following formula and descriptive examples will illustrate this invention but are not however, to be construed to limit it thereto.

EXAMPLE 1 ll-dimethylamino-10,5-(epoxymethano)-10,1l-dihydro- SH-dibenzo[a,d]cyclohepten-13-one Finely powdered 11-bromo-10,5-(epoxymethano)-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-13-one (15.0 g.) is added in small portions to anhydrous dimethylamine (50 ml.). The mixture is stirred for 4 hours under reflux conditions. The excess of the amine is then evaporated and the residual matter is triturated with water. The water-insoluble material thus obtained is recrystallized from methanol to give the title product, with M.P. 152- 154 C. Elemental analysis confirms the empirical for- 1111113 CHI-117N02- Treatment of the title compound with a molar excess of oxalic acid in ether gives the oxalate salt of 11-dimethylamino-10,5-(epoxymethano) 10,11 dihydro-5H- dibenzo[a,d]cyclohepten-13-one. This material has M.P. 140-145" C. after recrystallization from methanol.

In a similar manner, but using diethylamine, dipropylamine, dibutylamine, dipentylamine, dihexylamine, N- methylpropylamine, N-butylpentylamine, N-ethylhexylamine, N-methylbenzylamine or N-propylphenethylamine in place of dimethylamine the corresponding ll-diethylamino-, 11-dipropylamino-, 11-dibutylamin0-, 11-dipentylamino-, 1 1-dihexylamino-, 1 1- (N-methylpropylamino) 11-(N-butylpentylamino)-, 1 l-(N-ethylhexylamino) 11- (N-methylbenzylamino)-, or ll-(N-propylphenethylamino) 10,5 (epoxymethano)-10,1l-dihydro-SH-dibenzo- [a,d]cyclohepten-13-one is obtained. Treatment of the latter compounds with hydrochloric, sulfuric, oxalic, maleic, or tartaric acids yields the corresponding hydrochloride, sulfate, oxalate, maleate, or tartrate salts.

EXAMPLE 2 11-piperidino-10,5-(epoxymethano)-10,1l-dihydro- SH-dibenzo [a,d] cyclohepten-13-one Finely powdered 11-bromo-10,5-(epoxymethano)-10, 1 l-dihydro-SH-dibenzo [a,d] cyclohepten-13-one (15.0 g.) is added with stirring to piperidine ml.). The mixture is stirred at room temperature over-night and processed as described in Example 1, to give the title product, M.P. 203-205 C. when recrystallized from isopropanol. Elemental analysis confirms the empirical formula from dioxane or chloroform is obtained. Elemental analysis confirms the empirical formula C H NO A geometrical isomer of the above title product is prepared in the following manner. Thus, a mixture of 10,11-

0d "0 Col! II. I. III.

epoxy-10,11-dihydro 5H dibenzo[a,d]cycloheptene-5- carboxylic acid (2.5 g.) prepared as described in Example 5, morpholine (2.0 g.) and xylene (10 ml.) is heated under reflux for 12 hours. The mixture is cooled and extracted with dilute hydrochloric acid. The acid extracts are rendered alkaline with sodium bicarbonate and the precipitate is crystallized from methanol to give a geometrical isomer of the above title compound with M.P. 172-174" C. In a similar manner, but using dimethylamine, diethylamine, dipropylamine, dibutylamine, dipentylamine, dihexylamine, N-methylpropylamine, N-butylpentylamine, N ethylhexylamine, N methylbenzylamine, N-propylphenethylamine, piperidine, or N-methylpiperazine in place of morpholine, geometrical isomers of the compounds described in Examples 1, 2, and 4 are also obtained.

EXAMPLE 4 1 1-N-methylpiperazino-1(LS-(epoxymethano) 10,1 1- dihydro-SH-dibenzo [a,d] cyclohepten-13-one In the same manner as described in Example 2, but using N-methylpiperazine in place of piperidine, the above title compound, with M.P. 180-182 C. when purified from isopropanol, is obtained. Elemental analysis confirms the empirical formula C H N O EXAMPLE 5 10,11-epoxy-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene-S-carboxylic acid Finely powdered 11-bromo-10,5-(epoxymethano)-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-13-one (19.7 g.) is added all at once to 10% aqueous sodium hydroxide solution (50 ml.) which is pre-heated to C. The mixture is stirred and kept at 90 C. for 35 minutes. The mixture is rapidly cooled and then acidified with dilute hydrochloric acid. The precipitate is collected, washed with water, dried and crystallized from ethyl acetate to give the title compound with M.P. 161163 C.

We claim:

1. ll-dimethylamino 10,5-(epoxymethano)-10,1l-dihydro-5H-dibenzo[a,d]cyclohepten-IB-one, as claimed in claim 6.

2. 11 piperidino-10,5-(epoxymethano)-10,1l-dihydro- 5H-dibenzo[a,d] cyclohepten 13 one, as claimed in claim 6.

3. ll-morpholino 10,5 (epoxymethano)-10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-13-one, as claimed in claim 6.

4. ll-N-methylpiperazino 10,5 (epoxymethano)-10, 11 dihydro 5H dibenzo[a,d]cyclohepten 13-one, as claimed in claim 6.

5. The oxalate salt of 1l-dimethylamino-10,5-(epoxymethano) 10,11 dihydro-5H-dibcnzo[a,d]cyclohepten 13-one, as claimed in claim 6.

6. A compound selected from the group of compounds of the formula wherein R and R are lower alkyl, benzyl, phenethyl, tri- ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner U.S. Cl. X.R. 

